Camel genomics and their applications

〔Review〕

Advances in camel genomics and their applications: A review

Sherif RAMADAN1, 2, Miho INOUE-MURAYAMA1

1Wildlife Research Center, Kyoto University, Kyoto 606-8203, Japan 2Faculty of Veterinary Medicine, Benha University, Moshtohor 13736, Egypt

1.Introduction confirm this fact (Schwartz and Dioli 1992; Fowler 1998). Taxonomy and history The family Camelidae comprised two main types (large and The origin of the Old World camelids traces back to the small camelids) distributed into three genera: Camelus, end of Eocene (40–45 mya), where the first ancestors of the Lama and Vicugna. The small camelids originate from Andin camelid family were found in North America. After splitting Mountains of South America include two domestic species into New World (Lamini) and Old World (Camelini) camels, (lama and alpaca) and two wild species (guanaco in genus the latter migrated via the Bering land bridge to the eastern Lama, and vicuna in genus Vicugna). The large camelids are hemisphere (Janis et al. 1998; Ji et al. 2009; Wu et al. 2014, represented by two domesticated species, the one-humped 2015). Camel domestication was believed to begun in the camel (dromedary) and the two-humped camel (Bactrian), Arabian Peninsula around 3000 BC (Mikesell 1955). Since the first are living in the hot arid lands from North of Africa then it has dispersed to the whole African via Horn of Africa and eastern part of Asia, the second in the cold steppes and (Gifford-Gonzalez and Hanotte 2011). Camels facilitated the deserts in Central Asia. Also in the desert Gobi there is still a trading and cultural dialog between three continents by population of wild Bactrian camels classified as Camelus connecting and helping in the expansion of civilizations (e.g. ferus (Rao et al. 1970; Fowler 1998). The dromedary camel Roman Empire, Arab). has been extinct in the wild for several hundred years. There Camel is belonging to Camelidae family, order are no wild herds in existence in the native lands of the Artiodactyla (even-toed ungulates), sub-order tylopoda Middle East and Asia where they first came to be, but some (animals with padded feet)(Figure1). In spite the camel is a escaped domestic animals roam Australia (Roth and Merz ruminating animal, it is not a ruminant. Differences such as 1997). According to latest studies worldwide total camel foot anatomy, stomach system and the absence of horns population is 24.7 million head and the largest population has been found in Somalia (7 million). Eighty nine and fourteen different camel breeds of dromedary and Bactrian respectively are currently listed on FAO DAD-IS data-base (FAO 2016). An evolutionary history reconstructed for the family Camelidae based on cytb sequences suggested that the split of Bactrian and dromedary may have occurred in North America before the tribe Camelini migrated from North America to Asia (Cui et al. 2007). Mitochondrial cytb gene analyses from domestic and wild Bactrian camels revealed that the extant wild two-humped camel may not share a common ancestor with the domestic Bactrian camel

Correspondence: Miho Inoue-Murayama, Wildlife Research Center of Kyoto University, Tanaka Sekiden-cho, Sakyo, Kyoto 606-8203, Japan. Figure 1 Classification of the Camelidae family (e-mail: [email protected]) Figure 1 Classification of the Camelidae family

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and they are not the same subspecies at least in their developed thirty STR loci by sequencing dromedary genome maternal origins, and the extant wild camel is a separate at low coverage utilizing Roche and Illumina platforms. The lineage but not the direct progenitor of the domestic Bactrian number of alleles ranged from 1 to 3 while polymorphic camel (Ji et al. 2009; Silbermayr et al. 2010). In addition, information content averaged 0.38. Prasad et al. (2014) mtDNA sequence analysis of ancient DNA proved to be validated 374 SNPs based on a set of 672 dromedary and crucial in resolving domestication processes in dromedaries Bactrian camels using golden gate assay of Illumina. (Almathen et al. 2016). Phylogenetic study based on complete mitochondrial genomes excluding the control The camel, a multipurpose animal region suggested that the C. ferus and Lama pacos may Camel is a multipurpose animal. It can be used for occurred much earlier than what was deduced from the fossil milk, meat and wool production, for transportation, racing record (Cui et al. 2007). contests, tourism, agricultural work, and for beauty contest. A set of microsatellites were established in New World In Egypt for example, there are different dromedary camel camelids successfully amplified in the Camelini breeds used for different purposes; Maghrabi used for milk (Mariasegaram et al. 2002) and was applied to study the and meat production, Sudani and Somali for racing and genetic distance between Mongolian and Chinese domestic Falahi or Baladi for agricultural works as shown in Table 1 Bactrian camels (Jianlin et al. 2004). Sadder et al. (2015) and Figure 2 (Wardeh et al. 1991). The camel racing is an

Table 1 Egyptian camel breeds and purposes of each breed Breed Main purposes for each breed Maghrabi Dual-purpose, for meat and milk Somali Common for riding and racing Sudani Common for riding and racing Falahi or Baladi Transportation and agricultural operations Mowaled Hybrid between Maghrabi and Falahi

A B

C D

Figure 2 Photos show Egyptian dromedary camel breeds; A: Maghrabi, B: Hand milking of Maghrabi during calf sucking C: Sudani, and D: Somali

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important cultural event in the Arabian Peninsula and 20.251, 20.714 and 20.864 for the Bactrian, dromedary becomes popular also in Africa. The dromedary camel has in camels and alpaca genomes respectively (Wu et al. 2014, average 40 km/h speed but Bactrian camel racing speed has 2015). Functional analyses of the gene sets indicated that 27.2 km/h (Biichee 1998). The tourism attraction is on >91% of the genes were functionally annotated in each development, not only for riding on beach, dunes or around genome. The estimated divergence time between Camelini the pyramids in Egypt, but also for festival, fantasia and and Lamini was 16.3 while between Bactrian and dromedary other spectacles like the dancing camel at Pushkar fear in was 4.4 million years ago (Wu et al. 2014, 2015). India (Faye 2015). Camel milk is rich in insulin and insulin- The high quality genome sequences of the Bactrian, like proteins. Camel insulin, unlike the insulin contained dromedary camels and alpaca in addition to comparative within other animal milks, is contained within micelles and genomic analyses provided new insights into the adaptations is thus protected from digestion and proteolysis in the upper of camels to the harsh desert environment. Many genes gastrointestinal tract (Agrawal et al. 2011; Malik et al. related to metabolism are under accelerated evolution in the 2012). Camel milk is rich in lactoferrin and immunoglobulin camel compared with other even-toed ungulates such as with potent antimicrobial and anti-inflammatory properties, cattle. Genes involved in energy storage and production including bacterial inhibition, antiviral effects (HCV, HIV), capacities, immune and stress responses of camel were antifungal, antioxidant, anti-inflammatory and anti-cancer evolved more rapidly in the camels than in cattle. High actions (Konuspayeva et al. 2007; Alhaider et al. 2013; blood glucose levels and a diet loaded with high salt are Habib et al. 2013; Ismael et al. 2013; Kanwar et al. 2015). considered adaptation mechanisms that may help camels to This review will give an overview about the molecular survive in driest and harshest condition. The camel rapidly genetic studies performed over the past years, and deals with evolving genes include some that regulate insulin signaling molecular markers and their application in versatile aspects pathways, salt metabolism and also duplications of genes that will prove beneficial for researchers and scientists to which play critical roles in sodium reabsorption and water undertake further research to improve camel health and balance in the kidney (Jirimutu et al. 2012; Burger and production. Palmieri 2014; Wu et al. 2014, 2015; Almathen et al. 2016; Fitak et al. 2016). The identification of key genes involved Application of molecular markers in camel in the adaptation to the desert environment may have genetic research applications in breeding programs and may provide some Genetic improvement of livestock has been mainly perspective for disease-resistance research in different depending upon the selective breeding with superior animal species. Future studies on camel genomes and phenotypes. The use of molecular genetic techniques in transcriptomes may contribute to a detailed understanding of association with conventional animal breeding tools are these important physiological mechanisms with relevance to important to balance the process of selection and thus to human medical conditions (for example, the links between optimize the animal breeding program (Olesen et al. 1999; sodium metabolism and hypertension, hyperglycemia and Beuzen et al. 2000). In this review we will summarize report diabetes, fat metabolism and obesity, and dust and of camel genome SNPs and their relation with different respiratory diseases). traits. 3. Molecular markers for camel milk quality 2. Genome sequence information to and production unravel the camel’s adaptation to harsh Camels used for milk production are mainly belonging to desert environment dromedaries (Zhang et al. 2005). In 2010 about 5.25 million First draft whole genomes of the Old World camelids camels were producing 2.12 million tons of milk. The greatest have recently been published (Jirimutu et al. 2012; Burger dairy camel population worldwide is found in the North East and Palmieri 2014; Wu et al. 2014, 2015; Almathen et al. African countries including Somalia, Ethiopia and Sudan 2016; Fitak et al. 2016). The assembled genome sizes were (El-Agamy 2006). The casein fraction of camel milk composes 2.01, 2.01 and 2.05 GB while the annotated genes were 52-89% of total milk protein (Al-Haj and Al-Kanhal 2010) and

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distributes into four fractions: αs1-, αs2-, β-, and κ-CN and a synonymous SNP (G/A) in exon 4. For Bactrian camels the encoded by four genes, CSN1S1, CSN1S2, CSN2 and CSN3, nucleotide analysis showed one SNP (T/C) in exon 4. respectively (Kappeler et al. 1998; El-Agamy 2006).The β-casein Khabiri et al. (2014ab) sequenced 1,112 bp of is the most abundant protein in camel milk and it is encoded by promoter region of k-casein gene plus the first 100 bp from CSN2 gene. The nucleotide sequence of the whole β-casein- exon 1 and found 4 and 3 haplotypes in Bactrian and encoding gene (CSN2) plus 2141 bp at the 5′-flanking region in dromedary camels respectively. They found 14 transcription dromedary camels and the promoter region and the complete factors binding sites, where four of them (C/EBP-α, OCT1, cDNA in Bactrian camel were determined by (Pauciullo et al. MGF/STAT5 and TPB) almost perfectly conserved. Othman 2014). A total of 46 polymorphic sites had been detected. The et al. (2016) amplified 488-bp of κ-casein gene in 50 transition g.2126A>G falls within the TATA-box of dromedary Maghrabi breed samples reared in Egypt and digested them CSN2 promoter with a putative influence on the transcription with AluI endonuclease. They observed three genotypes; CC factor binding activity. The frequency of the G allele was 0.35 in (12%), TT (48%) CT (40%). Tanegonbady et al. (2016) a population of 180 she-camels belonging to 4 different ecotypes. studied the k-casein gene polymorphism and its relationship In the same population, a conservative SNP (g.4175C>A) was with some milk traits (fat, protein, lactose and solids non-fat found at the codon 7 of the signal peptide. Four SNPs were found milk) in 3 populations of Iranian camels (Bandar Turkman, in the Bactrian camel. The SNP c.666G>A was responsible for AqQala and Gonbad) and found a non-significant the amino acid change Met → Ile and it represented the first association between kappa-casein gene polymorphism and missense allele at the β-casein in camels (Pauciullo et al. 2014). milk production and composition traits.

In camel milk αs1-casein (22%) is considered the second main fraction after β- casein (65%) and before αs2- 4. Molecular markers for growth and meat casein (9.5%) and k-casein (3.5%) (El-Agamy 2006). A non- quality synonymous amino acid exchange (Glu → Asp) in the It is necessary to select genotypes with high growth and CSN1S1*C exon 5 was detected due to g.942G>T SNP. This meat quality for more contribution of camels to the SNP can differentiate between the two protein patterns of agricultural economy. Growth hormone (GH) is an anabolic αs1-casein (CSN1S1*A and CSN1S1*C) in two ecotypes of hormone which plays an important role in postnatal Sudanese camel (dromedary camel). The restriction of the 930 bp longitudinal growth, tissue growth, lactation, reproduction as PCR-product with SmlI endonuclease leads to two digested well as protein, lipid and carbohydrate metabolism (Dybus daughter bands of 456 bp and 474 bp when G base is 2002; Daverio et al. 2012). Six Sudanese camel breeds occurring (CSN1S1*A). The T nucleotide substitution (Kenani, Lahwee, Rashaidi, Anafi, Bishari and Kabbashi) destroys the restriction site of SmlI (Giambra et al. 2013). were genotyped for 419C>T SNP. The Bishari and Anafi Othman et al. (2016) found monomorphic pattern of α breeds that are classified as riding camels had slightly higher s1-casein after genotyping 50 Maghrabi camels reared in T allele frequencies than those of the other four breeds Egypt. which are classified as pack camels (Ishag et al. 2010). Ali Pauciullo et al. (2013) characterized the nucleotide et al. (2014) found a significant association of 450T>C SNP sequence of the whole κ-casein-encoding gene (CSN3) plus in GH gene and it was associated with the increased 1045 nucleotides at the 5 ′flanking region in dromedary estimated body weight. Both male and female Saheli Saudi camels. Highly conserved sequences located in the 5′ camels with the CC genotype had higher body weights than flanking region, have been found. 17 polymorphic sites have the CT and TT genotypes (P ≤ 0.05). Shawki et al. (2015) been detected, one of these (g.1029T>C) is responsible for found a SNP (419C>T) in the GH intron1 by genotyping 23 the creation of a new putative consensus sequence for the Maghrabi camels reared in Egypt. Abdel-Aziem et al. transcription factor HNF-1. Tahmoorespur et al. (2016) (2015) amplified a 613-bp fragment of camel GH in five showed that k-casein exon 4 sequence analyses of Iranian camel breeds reared in Egypt (Sudani, Somali, Mowaled, dromedary and Bactrian camels had high level homology in Maghrabi and Falahy). The result shows that the Maghrabi sequence and nucleotide content. The sequence analysis of breed that is classified as a dual purpose camels had higher dromedaries camels indicated one SNP (G/T) in intron 3 and frequency for allele C (0.75) than those in the other tested

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four breeds. Moreover, two SNPs (111G>C and 380G>A) been proposed as a fascinating model in the evolution of were detected in 630 bp of 5 UTR region of the GH gene in immune systems (Ciccarese et al. 2014). Transmissible 11 male dromedary camels and showed significance with spongiform encephalopathies (TSE), also known as prion many meat characters including dressing percentage with diseases, are a group of fatal neurodegenerative disorders of hump, dressing percentage with liver and number of fibers animals and humans. The etiology of TSE has not been fully hump (El-Kholy et al. 2016). The myogenic factors 5 elucidated but prions are believed to be the infectious agents (MYF5) gene has been reported to contribute to muscle (Chiesa and Harris 2001). The sequence of prion protein growth and development, therefore they are considered as gene (PRNP) in many animal species has been elucidated candidate genes for growth and meat quality related traits and they are found to be highly conserved in the course of (Sabourin and Rudnicki 2000; Maak et al. 2006). The MYF5 evolution (Yang et al. 2005). Little is known about PRNP of showed a non-synonymous SNP (377A>T) which resulted in domestic camels. The polymorphisms of PRNP in both Met → Lys amino acids change. This SNP was found to be species of camels were observed in codons 16 (Ala → Val), correlated with both carcass width at brisket and fat 17 (Met → Thr), 120 (Asn → Ser), 176 (Arg → Lys), 215 thickness of longissimus dorsi muscle (El-Kholy et al. (Ile → Val), 234 (Ser → Tyr), 237 (Tyr → Ser), and 239 2016). Hedayat-Evrigh et al. (2016) found two non- (Gln → Gly) by comparing with other ruminants (Xu et al. synonymous SNPs in MYF5 exon 1 which resulted in Ser 2012). In comparison to other mammalians, all camels → Asn and Trp → stop codon amino acid changes possessed an amino acid deletion at position 71 of amino respectively. acid sequence of PRNP gene; the amino acid G has been Myostatin (MSTN), also called growth differentiation deleted from this position. The existence of such genetic factor-8 (GDF-8) a negative regulator of skeletal muscle variations must be taken into consideration, if they are found development in mammals, represents a key target for genetic to be related to the host resistance against the prion disease investigations in meat-producing animals (Grobet et al. (Tahmoorespur and Jelokhani-Niaraki 2014). 1997; Gonzalez-Cadavid and Bhasin 2004). Myostatin gene The major histocompatibility complex (MHC) is a is highly conserved in camels. Shah et al. (2008) amplified genomic region containing immune response genes, which 256 bp of exon 1 among six Pakistani camel breeds play a crucial role in host and pathogen interactions. Studies (Marecha, Dhatti, Larri, Kohi, Sakrai and Cambelpuri) and of MHCs in different model species contribute to our found no polymorphism. Interestingly, only 3 variant sites in understanding of mechanisms of immunity, diseases and the first intron (486G/C, 798G/A, 799C/T) were detected in their evolution (Meyer and Thomson 2001). Physical the 3.6 kb of nucleotide sequence of MSTN gene spanning mapping located the MHC region to the chromosome 20 in the three exons and part of the three introns, 5UTR and 3 dromedary camels. DRA, DRB, DQA and DQB exon 2 UTR regions by Muzzachi et al. (2015) in 22 dromedary sequences encoding the antigen binding site of the camels from three different African populations (Tunisia, corresponding class II antigen presenting molecules showed Egypt, and Algeria). Leptin (LEP) and Calpain (CAPN1) high degree of sequence similarity and extensive allele have been considered as two candidate genes for carcass sharing across the three camels species. The DRA locus was performance and meat quality traits in the farm animals found to be polymorphic, with three alleles shared by all (Goll et al. 2003; Nkrumah et al. 2006). Tahmoorespur and three species. The extent of molecular diversity of MHC Shojaei (2013) amplified 471 bp and 787 bp from LEP and class II genes seems to be substantially lower in Old World CAPN1 genes respectively. They found no polymorphism camels than in other mammalian species (Plasil et al. 2016). among the 25 studied Iranian native camels, and also BoLA-DRB3 gene is responsible for the differences in the between dromedary and Bactrian camels. susceptibility to infectious disease in mammals and is considered more-appropriate for comparative evolutionary 5. Molecular markers for immunity and studies. Hussain et al., 2016 had detected 10 polymorphic disease resistance sites of BoLA-DRB3 exon 2 gene in 20 individuals of The Camelidae species occupy a peculiar niche within Pakistani camel breeds. Ten identified haplotypes showed the adaptive immune response and the camel lineage has haplotype diversity 0.879 and nucleotide diversity 0.0145.

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The detected polymorphic sites might be related to the (FSH) and luteinizing hormone (LH) are complex variability in the immune responsiveness of different heterodimer glycoproteins. The effects of the two individuals to particular pathogens (Hussain et al. 2016). gonadotropins on ovarian development are mediated by their For the first time in a mammalian organism, it was receptors (FSHR and LHR). These receptors belong to the shown that T cell receptor evolution has been favored in the members of the GTP-binding protein super-family dromedary by mutation in the productively rearranged (McFarland et al. 1989). Jelokhani-Niaraki et al. (2015) gamma (TRG) and delta (TRD) genes, thus contributing to found one SNP (319 C/T) in FSHR gene but no polymorphic the repertoire diversity of heterodimer. The T cell receptor site was found in LHR gene among 25 Iranian dromedary have evolved in the dromedary by mutation in the gamma camels. By comparing FSHR and LHR sequences of (TRG) and delta (TRD) genes and the diversity was generated dromedary with Bactrian there was one SNP in FSHR (319 by mutations, both clonal expansion and selection seem to be C/T) and in LHR (205 C/T) genes. strictly related to an enhanced structural stability of the ɤδ subunits (Ciccarese et al. 2014; Antonacci et al. 2015). 8. Conclusion The new era of omics technology provides us with 6. Molecular markers for camel racing genomic charts as well as genetic variations among Traditionally, the sport of camel racing was regarded as individuals and groups that may prove beneficial processing entertainment associated with the Bedouin festivals in the as well as analysis and integration of a large amount of data. Middle East region. Today, camel racing is a multi-million Thereby omics technology will provide valuable information dollar industry with regular race events being linked to regarding the precision of selection of molecular markers in extensive training and scientific breeding programs. Camel the near future. Identification and use of molecular markers racing is a popular sport in the Middle East region, where for camel milk quality and production traits, disease the demand is high for racing camels with higher stamina resistance, and thermo-tolerance will ensure better and endurance. Devising a technique to measure oxidative productivity of camels and subsequently human health. Also, capacity and endurance in camels should be useful (Wilson markers for fertility and carcass quality traits ensure faster 1999; Soman and Tinson 2016). and preferred growth in camels. Moreover, molecular Al-Harbi and Amer (2012) found low intensity band marker for improvement of temperament and personality patterns of the mitochondrial malate dehydrogenase (Mdh) will ensure better management, production and welfare of and malic (ME) iso-enzymes in dromedary camels for camels. Apart from these, the use of different markers such production than in dromedary camels for racing. They as microsatellites for assessment of biodiversity will help the concluded that mitochondrial Mdh and ME iso-enzymes conservation of camel populations. Integration of were useful as bioenergetic enzyme necessary for racing information from all sources along with a search for direct ability. The different expressions are indications of the markers and finding their causative sites for the QTL is difference in the physiological adaptations of both camel required. Finally, in light of ongoing global warming and the breeds and are not for a systematic value (Al-Harbi and increasing incidence of droughts, these camelid genomes are Amer 2012). The ratio of mitochondrial DNA (mtDNA) to valuable resources for studying biological adaptations to nuclear DNA (nDNA) is often used as an estimate for the environmental changes. metabolic status of the tissue. A greater quantity of mitochondria per unit of tissue translates into greater Acknowledgements oxidative capacity and endurance. Soman and Tinson (2016) We would like to express our thanks to Egyptian found that the racing camels demonstrated a higher mtDNA/ Ministry of Higher Education who funded Sherif Ramadan nDNA ratio compared with dairy camels. during his stay in Kyoto University. This study was supported in part by Kyoto University Supporting program 7. Molecular markers for reproductive for interaction-based initiative team studies (SPIRITS) to traits MI-M. We thank Dr. Hassan EL-Metwaly from Camel The two gonadotropins, follicle-stimulating hormone Research Department, Animal Production Research Institute,

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